Trematocidal Synthetic Perioxides

杀吸虫合成过氧化物

• 批准号: 7648067
• 负责人: Jonathan L Vennerstrom
• 金额: $ 15.81万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648067
• 关键词: Acids; Acute; Adamantane; Address; Adolescent; Adult; Affect; Bile fluid; Biological Assay; Carboxylic Acids; Cells; Characteristics; Chemicals; Chronic; Clonorchis sinensis; Country; Cyclohexanes; Data; Disease; Dose; Drug Combinations; Drug Kinetics; Drug resistance; Ensure; Enzymes; Fasciola hepatica; Fascioliasis; Feedback; Goals; Hepatic; Hepatica; Human; In Vitro; Infection; Inhibitory Concentration 50; Investigation; Lead; Libraries; Liver diseases; Measures; Metabolic; Metabolism; Modeling; Molecular Target; Morbidity - disease rate; Muscle; Myoblasts; Oral; Parasites; Peroxides; Pharmaceutical Preparations; Plant Roots; Plasmodium falciparum; Praziquantel; Prevention; Prodrugs; Property; Protein Isoforms; Rattus; Resistance development; Rural; Screening procedure; Skeletal Muscle; Staging; Surface; Testing; Toxic effect; Treatment Efficacy; Vaccines; analog; base; cytotoxicity; design; disorder prevention; drug development; flexibility; foodborne; functional group; in vitro testing; in vivo; insight; novel; process optimization; public health relevance; research study; triclabendazole

DESCRIPTION (provided by applicant): Food-borne trematodiases affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of food-borne tremotodiases, effective drugs are the only practical means of morbidity control. Importantly, new drugs for these diseases are urgently needed as praziquantel and triclabendazole are the only drugs available and the development of resistance cannot be ignored, particularly in view of the large- scale use of praziquantel in many endemic countries. At the root of this project is our discovery that several synthetic peroxides also possess strong trematocidal activity. We propose to further explore the potential of synthetic peroxides as novel trematocidal drugs. The identification of a new, broad-spectrum, orally-active synthetic peroxide trematocidal drug development candidate will minimize drug-resistance and lead to superior treatment and control options for food-borne trematodiases. Essential characteristics of a new drug development candidate include an economically-feasible and scalable synthesis, excellent oral activity, low potential for toxicity and resistance development, broad spectrum of trematocidal activity, and high efficacy against all parasite stages in the vertebrate host. More specifically, our objective is to identify a drug development candidate with 100% worm burden reductions against juvenile and adult F. hepatica and C. sinensis at doses of < 100 mg/kg and with an excellent ADME profile (predicted ER < 0.30, CYP450 IC50s > 25 5M, oral BA > 30%). To address this overarching objective, we propose the following three specific aims: Specific Aim 1: To synthesize and characterize a focused and structurally diverse library of synthetic peroxides. Specific Aim 2: To assess trematocidal activity and selectivity of target synthetic peroxides against two major human food-borne trematode species, Fasciola hepatica and Clonorchis sinensis. Specific Aim 3: To determine metabolism and pharmacokinetic parameters and initiate mechanism of action studies for selected synthetic peroxides. PUBLIC HEALTH RELEVANCE Food-borne trematodiases, caused by infection with liver flukes, affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of these diseases, new drugs are urgently needed. Praziquantel and triclabendazole are the only drugs now available and the development of resistance cannot be ignored, particularly in view of the large-scale use of praziquantel in many endemic countries. In this proposal, we propose to identify a new broad-spectrum orally-active trematocidal drug development candidate.

描述（由申请人提供）：食源性的杂种会影响数亿人，尤其是发展中国家的农村贫困人口。由于目前无法使用疫苗，并且不太可能很快就可以预防食物鼻烟，因此有效的药物是发病率控制的唯一实际手段。重要的是，由于praziquantel和Triclabendazole是唯一可用的药物，因此迫切需要这些疾病的新药物，并且不容忽视抗药性，尤其是考虑到许多地方性国家大规模使用Praziquantel。该项目的根源是我们发现几种合成过氧化物也具有强大的巨质活性。我们建议进一步探索合成过氧化物作为新型巨质药物的潜力。鉴定出一种新的，广泛的，口服活跃的过氧化过氧化物巨大药物开发候选者的候选者将最大程度地减少药物耐药性，并为食源性的杂种症带来卓越的治疗和控制选择。新药开发候选者的基本特征包括经济上可行的可扩展合成，出色的口服活性，毒性和抵抗力发展的潜力低，巨大活性的广泛谱以及对脊椎动物宿主中所有寄生虫阶段的高效率。更具体地说，我们的目标是确定针对青少年和成人肝癌和成年hepatica和C. sinensis的药物开发候选者的剂量<100 mg/kg，并且具有出色的ADME概况（预测ER <0.30，CYP450，CYP450 IC50S> 25 5M，Oral Ba> 30％）。为了解决这个总体目标，我们提出以下三个特定目的：特定目的1：合成和表征集中且结构上多样化的合成过氧化物库。具体目的2：评估靶标合成过氧化物对两个主要的人类食物传播巨星物种，fasciola hepatica和clonorchis sinensis的巨大活性和选择性。特定目的3：确定代谢和药代动力学参数，并启动对选定合成过氧化物的作用研究机理。公共卫生相关性食品传播的杂种症是由肝漏气感染引起的，影响了数亿人，尤其是发展中国家的农村贫困人口。由于目前无法使用疫苗，并且不太可能很快就可以预防这些疾病，因此迫切需要新药。 praziquantel和triclabendazole是现在唯一可用的药物，抗药性的发展不容忽视，尤其是鉴于许多地方性国家大规模使用praziquantel。在此提案中，我们建议确定一种新的大光谱口腔活跃的杂种药物开发候选者。

项目成果

Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni.

• DOI: 10.1016/j.actatropica.2011.02.003
• 发表时间: 2011-04
• 期刊: ACTA TROPICA
• 影响因子: 2.7
• 作者: Kirchhofer, Carla;Vargas, Mireille;Braissant, Olivier;Dong, Yuxiang;Wang, Xiaofang;Vennerstrom, Jonathan L.;Keiser, Jennifer
• 通讯作者: Keiser, Jennifer

Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.

• DOI: 10.1021/jm100226t
• 发表时间: 2010-05-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhao Q;Vargas M;Dong Y;Zhou L;Wang X;Sriraghavan K;Keiser J;Vennerstrom JL
• 通讯作者: Vennerstrom JL

The activity of dispiro peroxides against Fasciola hepatica.

二螺过氧化物对肝片形吸虫的活性。

• DOI: 10.1016/j.bmcl.2011.07.024
• 发表时间: 2011
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Wang,Xiaofang;Zhao,Qingjie;Vargas,Mireille;Dong,Yuxiang;Sriraghavan,Kamaraj;Keiser,Jennifer;Vennerstrom,JonathanL
• 通讯作者: Vennerstrom,JonathanL

Tetrasubstituted pyrazinones derived from the reaction of praziquantel with N-bromosuccinimide.

由吡喹酮与N-溴代琥珀酰亚胺反应衍生的四取代吡嗪酮。

• DOI: 10.1016/j.tetlet.2014.06.083
• 发表时间: 2014
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Zhao,Qingjie;Wang,Chunkai;Ezell,EdwardL;Dong,Yuxiang;Vennerstrom,JonathanL
• 通讯作者: Vennerstrom,JonathanL